Carbamoyl hydrazine derivatives as formyl peptide modulators

ABSTRACT

The present invention relates to carbamoyl hydrazine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of the FPR receptor.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/977,296, filed on Apr. 9, 2014, the entire disclosure of each ofthese applications being incorporated herein by this reference.

FIELD OF THE INVENTION

The present invention relates to carbamoyl hydrazine derivatives,processes for preparing them, pharmaceutical compositions containingthem, and their use as pharmaceuticals as modulators of the N-formylpeptide receptor (FPR), including the N-formyl peptide receptor 2(FPR2). The invention relates specifically to the use of these compoundsand their pharmaceutical compositions to treat disorders associated withFPR modulation, such as FPR2 modulation.

BACKGROUND OF THE INVENTION

The FPR2 receptor is a G protein-coupled receptor that is expressed oninflammatory cells such as monocytes and neutrophils, as well as Tcells, and has been shown to play a critical role in leukocytetrafficking during inflammation and human pathology. FPR2 is anexceptionally promiscuous receptor that responds to a large array ofexogenous and endogenous ligands, including serum amyloid A (SAA),chemokine variant sCKβ8-1, the neuroprotective peptide human,anti-inflammatory eicosanoid lipoxin A4 (LXA4) andglucocorticoid-modulated protein annexin A1. FPR2 transducesanti-inflammatory effects of LXA4 in many systems, but it also canmediate the pro-inflammatory signaling cascade of peptides such as SAA.The ability of the receptor to mediate two opposite effects is proposedto be a result of different receptor domains used by different agonists(Parmentier, Marc et al., Cytokine & Growth Factor Reviews 17 (2006)501-519).

Activation of FPR2 by LXA4 or its analogs and by Annexin I protein hasbeen shown to result in anti-inflammatory activity by promoting activeresolution of inflammation which involves inhibition ofpolymorphonuclear neutrophil (PMN) and eosinophil migration and alsostimulating monocyte migration, enabling clearance of apoptotic cellsfrom the site of inflammation in a nonphlogistic manner. In addition,FPR2 has been shown to inhibit natural killer (NK) cell cytotoxicity andpromote activation of T cells, which further contributes todown-regulation of tissue damaging inflammatory signals. FPR2/LXA4interaction has been shown to be beneficial in experimental models ofischemia reperfusion, angiogenesis, dermal inflammation,chemotherapy-induced alopecia, ocular inflammation such asendotoxin-induced uveitis, corneal wound healing, re-epithelializationetc. FPR2 thus represents an important novel pro-resolutionary moleculartarget for the development of new therapeutic agents in diseases withexcessive inflammatory responses.

SUMMARY OF THE INVENTION

We have now discovered a group of novel compounds which are potent andselective FPR2 modulators. As such, the compounds described herein areuseful in treating a wide variety of disorders associated withmodulation of the FPR receptor, such as FPR2. The term “modulator” asused herein, includes but is not limited to: receptor agonist,antagonist, inverse agonist, inverse antagonist, partial agonist,partial antagonist.

This invention describes compounds of Formula I, which have FPR2receptor biological activity. The compounds in accordance with thepresent invention are thus of use in medicine, for example in thetreatment of humans with diseases and conditions that are alleviated byFPR modulation, such as FPR2 modulation.

In one aspect, the invention provides a compound having Formula I or theindividual enantiomers, diastereoisomers, zwitterions, tautomers or apharmaceutically acceptable salt thereof:

wherein:

-   -   R¹ is H, optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl,        optionally substituted C₃₋₈ cycloalkyl, optionally substituted        C₆₋₁₀aryl, optionally substituted heterocycle, halogen, —OR¹⁰,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —CN, —C(O)R¹¹, amine, amide, urea,        sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro,        phosphate or phosphonic acid;    -   R² is H, optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl,        optionally substituted C₃₋₈cycloalkyl, optionally substituted        C₆₋₁₀aryl, optionally substituted heterocycle, halogen, —OR¹⁰,        —C₂₋₆alkenyl, —C₂₋₆ alkynyl, —CN, —C(O)R¹¹, amine, amide, urea,        sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro,        phosphate or phosphonic acid;    -   R³ is H, optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl,        optionally substituted C₃₋₈cycloalkyl, optionally substituted        C₆₋₁₀aryl, optionally substituted heterocycle, halogen, —OR¹⁰,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —CN, —C(O)R¹¹, amine, amide, urea,        sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro,        phosphate or phosphonic acid;    -   R⁴ is H, optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl,        optionally substituted C₃₋₈cycloalkyl, optionally substituted        C₆₋₁₀aryl, optionally substituted heterocycle, halogen, —OR¹⁰,        —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, —CN, —C(O)R¹¹, amine, amide, urea,        sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro,        phosphate or phosphonic acid;    -   R⁵ is H, optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl,        optionally substituted C₃₋₈ cycloalkyl, optionally substituted        C₆₋₁₀aryl, optionally substituted heterocycle, halogen, —OR¹⁰,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —CN, —C(O)R¹¹, amine, amide, urea,        sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro,        phosphate or phosphonic acid;    -   R⁶ is H or optionally substituted C₁₋₆alkyl;    -   R⁷ is H or optionally substituted C₁₋₆alkyl;    -   R⁸ is H or optionally substituted C₁₋₆alkyl;    -   R⁹ is H or optionally substituted C₁₋₆alkyl;    -   a is 0, 1, 2 or 3;    -   R¹⁰ is —OH or optionally substituted C₁₋₆alkyl; and    -   R¹¹ is —OH, —OC₁₋₆alkyl or optionally substituted C₁₋₆alkyl;    -   with the proviso that the compound of Formula I is not of        structure:

In another aspect, the invention provides a compound represented byFormula I, wherein:

R¹ is H or halogen;R² is H or halogen;R³ is C₁₋₆haloalkyl or halogen;R⁴ is H or halogen;R⁵ is H or halogen;R⁶ is H or optionally substituted C₁₋₆alkyl;R⁷ is H or optionally substituted C₁₋₆alkyl;R⁸ is H or optionally substituted C₁₋₆alkyl;R⁹ is H or optionally substituted C₁₋₆alkyl;a is 0, 1, 2 or 3;

-   -   with the proviso that the compound of Formula I is not of        structure:

In another aspect, the invention provides a compound represented byFormula I, wherein:

R¹ is H or halogen;R² is H or halogen;R³ is C₁₋₆haloalkyl;R⁴ is H or halogen;R⁵ is H or halogen;R⁶ is H or optionally substituted C₁₋₆alkyl;R⁷ is H or optionally substituted C₁₋₆alkyl;R⁸ is H or optionally substituted C₁₋₆alkyl;R⁹ is H or optionally substituted C₁₋₆alkyl; anda is 0, 1, 2 or 3.

In another aspect, the invention provides a compound represented byFormula I, wherein:

R¹ is H or halogen;R² is H or halogen;R³ is halogen;R⁴ is H or halogen;R⁵ is H or halogen;R⁶ is H or optionally substituted C₁₋₆alkyl;R⁷ is H or optionally substituted C₁₋₆alkyl;R⁸ is H or optionally substituted C₁₋₆alkyl;R⁹ is H or optionally substituted C₁₋₆alkyl;a is 0, 1, 2 or 3;with the proviso that the compound of Formula I is not of structure:

In another aspect, the invention provides a compound represented byFormula I, wherein:

R¹ is H or halogen;R² is H or halogen;R³ is C₁₋₆haloalkyl or halogen;R⁴ is H or halogen;R⁵ is H or halogen;R⁶ is H or optionally substituted C₁₋₆alkyl;R⁷ is H or optionally substituted C₁₋₆alkyl;R⁸ is H or optionally substituted C₁₋₆alkyl;

R⁹ is H; and

a is 0, 1, 2 or 3.

In another aspect, the invention provides a compound represented byFormula I, wherein:

R¹ is H or halogen;R² is H or halogen;R³ is C₁₋₆haloalkyl or halogen;R⁴ is H or halogen;R⁵ is H or halogen;R⁶ is H or optionally substituted C₁₋₆alkyl;R⁷ is H or optionally substituted C₁₋₆alkyl;R⁸ is H or optionally substituted C₁₋₆alkyl;R⁹ is optionally substituted C₁₋₆alkyl;a is 0, 1, 2 or 3.with the proviso that the compound of Formula I is not of structure:

In another aspect, the invention provides a compound represented byFormula I, wherein:

R¹ is H or halogen;R² is H or halogen;R³ is C₁₋₆haloalkyl;R⁴ is H or halogen;R⁵ is H or halogen;R⁶ is H or optionally substituted C₁₋₆ alkyl;R⁷ is H or optionally substituted C₁₋₆ alkyl;R⁸ is H or optionally substituted C₁₋₆ alkyl;

R⁹ is H; and

a is 0, 1, 2 or 3.

In another aspect, the invention provides a compound represented byFormula I, wherein:

R¹ is H or halogen;R² is H or halogen;R³ is C₁₋₆haloalkyl;R⁴ is H or halogen;R⁵ is H or halogen;R⁶ is H or optionally substituted C₁₋₆ alkyl;R⁷ is H or optionally substituted C₁₋₆ alkyl;R⁸ is H or optionally substituted C₁₋₆ alkyl;R⁹ is optionally substituted C₁₋₆ alkyl; anda is 0, 1, 2 or 3.

In another aspect, the invention provides a compound represented byFormula I, wherein:

R¹ is H or halogen;

R² is H;

R³ is halogen or C₁₋₆haloalkyl;

R⁴ is H;

R⁵ is H or halogen;R⁶ is H or optionally substituted C₁₋₆alkyl;

R⁷ is H; R⁸ is H;

R⁹ is H or optionally substituted C₁₋₆alkyl; anda is 0 or 1.

In another aspect, the invention provides a compound represented byFormula I, wherein:

R¹ is H or halogen;R² is H or halogen;R³ is halogen;R⁴ is H or halogen;R⁵ is H or halogen;R⁶ is H or optionally substituted C₁₋₆alkyl;R⁷ is H or optionally substituted C₁₋₆alkyl;R⁸ is H or optionally substituted C₁₋₆alkyl;

R⁹ is H; and

a is 0, 1, 2 or 3.

In another aspect, the invention provides a compound represented byFormula I, wherein:

R¹ is H or halogen;R² is H or halogen;R³ is halogen;R⁴ is H or halogen;R⁵ is H or halogen;R⁶ is H or optionally substituted C₁₋₆alkyl;R⁷ is H or optionally substituted C₁₋₆alkyl;R⁸ is H or optionally substituted C₁₋₆alkyl;R⁹ is optionally substituted C₁₋₆alkyl;a is 0, 1, 2 or 3;with the proviso that the compound of Formula I is not of structure:

In another aspect, the invention provides a compound represented byFormula I, wherein:

R¹ is H or halogen;

R² is H;

R³ is halogen or C₁₋₆haloalkyl;

R⁴ is H;

R⁵ is H or halogen;R⁶ is H or optionally substituted C₁₋₆alkyl;R⁷ is H or optionally substituted C₁₋₆alkyl;R⁸ is H or optionally substituted C₁₋₆alkyl;R⁹ is H or optionally substituted C₁₋₆alkyl; anda is 0 or 1.

In another aspect, the invention provides a compound represented byFormula I, wherein:

R¹ is H or halogen;

R² is H;

R³ is halogen or C₁₋₆haloalkyl;

R⁴ is H;

R⁵ is H or halogen;R⁶ is H or C₁₋₆alkyl;R⁷ is H or C₁₋₆alkyl;R⁸ is H or C₁₋₆alkyl;R⁹ is H or C₁₋₆alkyl; anda is 0 or 1.

In another aspect, the invention provides a compound having Formula I,or the individual enantiomers, diastereoisomers, zwitterions, tautomersor a pharmaceutically acceptable salt thereof:

wherein:

-   -   R¹ is H, optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl,        optionally substituted C₃₋₈cycloalkyl, optionally substituted        C₆₋₁₀aryl, optionally substituted heterocycle, halogen, —OR¹⁰,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —CN, —C(O)R¹¹, amine, amide, urea,        sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro,        phosphate or phosphonic acid;    -   R² is H, optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl,        optionally substituted C₃₋₈cycloalkyl, optionally substituted        C₆₋₁₀aryl, optionally substituted heterocycle, halogen, —OR¹⁰,        —C₂₋₆alkenyl, —C₂₋₆ alkynyl, —CN, —C(O)R¹¹, amine, amide, urea,        sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro,        phosphate or phosphonic acid;    -   R³ is H, optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl,        optionally substituted C₃₋₈cycloalkyl, optionally substituted        C₆₋₁₀aryl, optionally substituted heterocycle, halogen, —OR¹⁰,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —CN, —C(O)R¹¹, amine, amide, urea,        sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro,        phosphate or phosphonic acid;    -   R⁴ is H, optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl,        optionally substituted C₃₋₈cycloalkyl, optionally substituted        C₆₋₁₀aryl, optionally substituted heterocycle, halogen, —OR¹⁰,        —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, —CN, —C(O)R¹¹, amine, amide, urea,        sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro,        phosphate or phosphonic acid;    -   R⁵ is H, optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl,        optionally substituted C₃₋₈ cycloalkyl, optionally substituted        C₆₋₁₀aryl, optionally substituted heterocycle, halogen, —OR¹⁰,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —CN, —C(O)R¹¹, amine, amide, urea,        sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro,        phosphate or phosphonic acid;    -   R⁶ is H or optionally substituted C₁₋₆alkyl;    -   R⁷ is H or optionally substituted C₁₋₆alkyl;    -   R⁸ is H or optionally substituted C₁₋₆alkyl;    -   R⁹ is H or optionally substituted C₁₋₆alkyl;    -   a is 0, 1, 2 or 3;    -   R¹⁰ is —OH or optionally substituted C₁₋₆alkyl; and    -   R¹¹ is —OH, —OC₁₋₆alkyl or optionally substituted C₁₋₆alkyl;    -   provided that when a is 1, at least one of R⁶, R⁷ and R⁹ is not        H.

In another aspect, the invention provides a compound represented byFormula I, wherein:

R¹ is H or halogen;

R² is H;

R³ is halogen or C₁₋₆haloalkyl;

R⁴ is H;

R⁵ is H or halogen;R⁶ is H or optionally substituted C₁₋₆alkyl;R⁷ is H or optionally substituted C₁₋₆alkyl;R⁸ is H or optionally substituted C₁₋₆alkyl;R⁹ is H or optionally substituted C₁₋₆alkyl; anda is 0 or 1;provided that when a is 1, at least one of R⁶, R⁷ and R⁹ is not H.

In another aspect, the invention provides a compound represented byFormula I, wherein:

R¹ is H or halogen;

R² is H;

R³ is halogen or C₁₋₆haloalkyl;

R⁴ is H;

R⁵ is H or halogen;R⁶ is H or C₁₋₆alkyl;R⁷ is H or C₁₋₆alkyl;R⁸ is H or C₁₋₈alkyl;R⁹ is H or C₁₋₈alkyl; anda is 0 or 1;provided that when a is 1, at least one of R⁶, R⁷ and R⁹ is not H.

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 6 carbon atoms (i.e.,C₁₋₆alkyl). One or more methylene (CH₂) groups of the alkyl can bereplaced by oxygen, sulfur, carbonyl, sulfoxide, sulfonyl, or by adivalent C₃₋₆ cycloalkyl. One or more methine (CH) groups of the alkylcan be replaced by nitrogen. Alkyl groups are optionally substitutedwith one or more groups including, but not limited to: halogen,hydroxyl, cycloalkyl, heterocycle, aryl, ether, amine, nitro, nitrile,amide, sulfonamide, ester, aldehyde, carboxylic acid, ketone, sulfonicacid, phosphonic acid, and/or phosphoric acid.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms (i.e., C₃₋₈cycloalkyl) derivedfrom a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclicor polycyclic. Cycloalkyl groups are optionally substituted with one ormore groups including, but not limited to: halogens, hydroxyls,cycloalkyls, heterocycles, aryls, ethers, amines, nitros, nitriles,amides, sulfonamides, esters, aldehydes, carboxylic acids, ketones,sulfonic acids, phosphonic acids, phosphoric acids.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms (i.e., C₃₋₈cycloalkenyl) derivedfrom a saturated cycloalkyl having one or more double bonds.Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groupsare optionally substituted by one or more groups including, but notlimited to halogens, hydroxyls, cycloalkyls, heterocycles, aryls,ethers, amines, nitros, nitriles, amides, sulfonamides, esters,aldehydes, carboxylic acids, ketones, sulfonic acids, phosphonic acids,phosphoric acids.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms (i.e., C₂₋₆ alkenyl),derived from a saturated alkyl, having at least one double bond. C₂₋₆alkenyl can be in the E or Z configuration. Alkenyl groups areoptionally substituted with C₁₋₃alkyl.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms (i.e., C₂₋₆ alkynyl)derived from a saturated alkyl, having at least one triple bond.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or non-saturated,containing at least one heteroatom selected from O, N and S, orcombinations of at least two thereof, interrupting the carbocyclic ringstructure. The heterocyclic ring can be interrupted by one or more C═O;the S heteroatom can be oxidized. Heterocycles can be monocyclic orpolycyclic. Heterocyclic ring moieties are optionally substituted withone or more groups including, but not limited to: halogens, hydroxyls,cycloalkyls, heterocycles, aminos, nitros, nitirles, amides, ethers,esters, ketones, carboxylic acids, aldehydes, sulfonamides, sulfonicacids, phosphonic acids, phosphoric acids.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms by removal of one hydrogen (i.e., C₆₋₁₀aryl). Aryl groups areoptionally substituted by one or more groups including, but not limitedto: halogens, hydroxyls, cycloalkyls, heterocycles, aminos, nitros,nitirles, amides, ethers, esters, carboxylic acids, aldehydes, ketones,sulfonamides sulfonic acids, phosphonic acids, phosphoric acids. Arylcan be monocyclic or polycyclic.

The term “amine” as used herein, represents a group of formula“—NR^(x)R^(y)”, wherein R^(x) and R^(y) can be the same or independentlyH, alkyl, aryl, cycloalkyl, cycloalkenyl or heterocyclyl, as definedabove.

The term “amide” as used herein, represents a group of formula“—C(O)N(R^(x))(R^(y))” or —“NR^(x)C(O)R^(y)” wherein R^(x) and R^(y) canbe the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl orheterocyclyl, as defined above.

The term “sulfonamide” as used herein, represents a group of formula“—S(O)₂N(R^(x))(R^(y))” or “—NR^(x)S(O)₂R^(y)” wherein R^(x) and R^(y)can be the same or independently H, alkyl, aryl, cycloalkyl,cycloalkenyl or heterocyclyl, as defined above.

The term “ester” as used herein, represents a group of formula“—C(O)O(R^(x))”, wherein R^(x) is alkyl, aryl, cycloalkyl, cycloalkenylor heterocyclyl, as defined above.

The term “aldehyde” as used herein, represents a group of formula“—C(O)H”.

The term “ketone” as used herein, represents a group of formula“—C(O)R^(x)” wherein R^(x) is alkyl, aryl, cycloalkyl, cycloalkenyl orheterocyclyl, as defined above.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “amino” as used herein, represents a group of formula “—NH₂”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)—”.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O-”.

The term “sulfonyl” as used herein, represents a group of formula“—SO₂-”.

The term “sulfate” as used herein, represents a group of formula“—OS(O)₂O⁻”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “sulfoxide” as used herein, represents a group of formula“—S(O)—”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—(O)P(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The term “nitro” as used herein, represents a group of formula “—NO₂”.

The term “nitrile” as used herein, represents a group of formula “—CN”.

The term “ether” as used herein, represents a group of formula “—OR^(x),wherein R^(x) is alkyl, aryl, cycloalkyl, cycloalkenyl or heterocyclyl,as defined above.

Some compounds of the invention are:

-   4-{2-[(4-Bromo-2-fluorophenyl)carbamoyl]-1-propylhydrazinyl}-4-oxobutanoic    acid;-   Ethyl    4-{2-[(4-bromo-2-fluorophenyl)carbamoyl]-1-propylhydrazinyl}-4-oxobutanoate;-   Ethyl    4-{2-[(4-bromophenyl)carbamoyl]-1-butylhydrazinyl}-4-oxobutanoate;-   4-[1-(2-Methylpropyl)-2-{[4-(trifluoromethyl)phenyl]carbamoyl}hydrazinyl]-4-oxobutanoic    acid;-   4-oxo-4-(1-Propyl-2-{[4-(trifluoromethyl)phenyl]carbamoyl}hydrazinyl)butanoic    acid;-   Ethyl    4-[1-(2-methylpropyl)-2-{[4-(trifluoromethyl)phenyl]carbamoyl}hydrazinyl]-4-oxobutanoate;-   Ethyl    4-oxo-4-(1-propyl-2-{[4-(trifluoromethyl)phenyl]carbamoyl}hydrazinyl)    butanoate;-   4-{2-[(4-Bromo-2-fluorophenyl)carbamoyl]-1-(2-methylpropyl)hydrazinyl}-4-oxobutanoic    acid;-   Ethyl    4-{2-[(4-bromo-2-fluorophenyl)carbamoyl]-1-(2-methylpropyl)hydrazinyl}-4-oxobutanoate;-   4-{2-[(4-Bromophenyl)carbamoyl]-1-(2-methylpropyl)hydrazinyl}-4-oxobutanoic    acid;-   Ethyl    4-{2-[(4-bromophenyl)carbamoyl]-1-(2-methylpropyl)hydrazinyl}-4-oxobutanoate;-   4-{2-[(4-Bromophenyl)carbamoyl]hydrazinyl}-2,2-diethyl-4-oxobutanoic    acid;-   2-(2-{2-[(4-Bromophenyl)carbamoyl]hydrazinyl}-2-oxoethyl)-2-propylpentanoic    acid;-   Methyl    2-(2-{2-[(4-Bromophenyl)carbamoyl]hydrazinyl}-2-oxoethyl)-2-propylpentanoate;-   4-{2-[(4-Bromophenyl)carbamoyl]hydrazinyl}-2,2-dimethyl-4-oxobutanoic    acid;-   3-{2-[(4-Bromophenyl)carbamoyl]hydrazinyl}-2,2-dimethyl-3-oxopropanoic    acid; and-   Ethyl 3-{2-[(4-Bromophenyl)carbamoyl]hydrazinyl}-3-oxopropanoate.

Some compounds of Formula I and some of their intermediates have atleast one asymmetric center in their structure. This asymmetric centermay be present in an R or S configuration, said R and S notationcorresponding to the rules described in Pure Appli. Chem. (1976), 45,11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid andthe like; or an organic acid such as for example, acetic acid,hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonicacid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinicacid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid,citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonicacid, formic and the like (Handbook of Pharmaceutical Salts, P. HeinrichStahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich,2002, 329-345).

The base addition salt form of a compound of Formula I that occurs inits acid form can be obtained by treating the acid with an appropriatebase such as an inorganic base, for example, sodium hydroxide, magnesiumhydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like;or an organic base such as for example, L-Arginine, ethanolamine,betaine, benzathine, morpholine and the like. (Handbook ofPharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds),Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345).

The compounds of the invention are indicated for use in treating orpreventing conditions in which there is likely to be a componentinvolving the FPR, including FPR2.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of the FPR, includingFPR2. Such methods can be performed, for example, by administering to asubject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

Therapeutic utilities of the FPR modulators, including those whichmodulate FPR2, are ocular inflammatory diseases including, but notlimited to, wet and dry age-related macular degeneration (ARMD),uveitis, dry eye, keratitis, allergic eye disease and conditionsaffecting the posterior part of the eye, such as maculopathies andretinal degeneration including non-exudative age related maculardegeneration, exudative age related macular degeneration, choroidalneovascularization, diabetic retinopathy (proliferative), retinopathy ofprematurity (ROP), acute macular neuroretinopathy, central serouschorioretinopathy, cystoid macular edema, and diabetic macular edema;infectious keratitis, herpetic keratitis, corneal angiogenesis,lymphangiogenesis, retinitis, and choroiditis such as acute multifocalplacoid pigment epitheliopathy, Behcet's disease, birdshotretinochoroidopathy, infectious (syphilis, lyme, tuberculosis,toxoplasmosis), intermediate uveitis (pars planitis), multifocalchoroiditis, multiple evanescent white dot syndrome (mewds), ocularsarcoidosis, posterior scleritis, serpiginous choroiditis, subretinalfibrosis and uveitis syndrome, Vogt-Koyanagi- and Harada syndrome;vascular diseases/exudative diseases such as retinal arterial occlusivedisease, central retinal vein occlusion, cystoids macular edema,disseminated intravascular coagulopathy, branch retinal vein occlusion,hypertensive fundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinalvein occlusion, papillophlebitis, central retinal artery occlusion,branch retinal artery occlusion, carotid artery disease (CAD), frostedbranch angiitis, sickle cell retinopathy and other hemoglobinopathies,angioid streaks, familial exudative vitreoretinopathy, and Ealesdisease; traumatic/surgical conditions such as sympathetic ophthalmia,uveitic retinal disease, retinal detachment, trauma, conditions causedby laser, conditions caused by photodynamic therapy, photocoagulation,hypoperfusion during surgery, radiation retinopathy, and bone marrowtransplant retinopathy; proliferative disorders such as proliferativevitreal retinopathy and epiretinal membranes, and proliferative diabeticretinopathy; infectious disorders such as ocular histoplasmosis, oculartoxocariasis, presumed ocular histoplasmosis syndrome (PONS),endophthalmitis, toxoplasmosis, retinal diseases associated with HIVinfection, choroidal disease associate with HIV infection, uveiticdisease associate with HIV infection, viral retinitis, acute retinalnecrosis, progressive outer retinal necrosis, fungal retinal diseases,ocular syphilis, ocular tuberculosis, diffuse unilateral subacuteneuroretinitis, and myiasis; genetic disorders such as retinitispigmentosa, systemic disorders with associated retinal dystrophies,congenital stationary night blindness, cone dystrophies, Stargardt'sdisease and fundus flavimaculatus, Best's disease, pattern dystrophy ofthe retinal pigmented epithelium, X-linked retinoschisis, Sorsby'sfundus dystrophy, benign concentric maculopathy, Bietti's crystallinedystrophy, and pseudoxanthoma elasticum; retinal tears/holes such asretinal detachment, macular hole, and giant retinal tear; tumors such asretinal disease associated with tumors, congenital hypertrophy of theretinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigment epitheliitis, systemicinflammatory diseases such as stroke, coronary artery disease,obstructive airway diseases, HIV-mediated retroviral infections,cardiovascular disorders including coronary artery disease,neuroinflammation, neurological disorders, pain and immunologicaldisorders, asthma, allergic disorders, inflammation, systemic lupuserythematosus, psoriasis, CNS disorders such as Alzheimer's disease,arthritis, sepsis, inflammatory bowel disease, cachexia, anginapectoris, post-surgical corneal inflammation, blepharitis, MGD, dermalwound healing, corneal wound healing burns, rosacea, atopic dermatitis,acne, psoriasis, seborrheic dermatitis, actinic keratoses, viral warts,photoaging rheumatoid arthritis and related inflammatory disorders,alopecia, glaucoma, branch vein occlusion, Best's vitelliform maculardegeneration, retinitis pigmentosa, proliferative vitreoretinopathy(PVR), and any other degenerative disease of either the photoreceptorsor the RPE (Perretti, Mauro et al. Pharmacology & Therapeutics 127(2010) 175-188.)

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated byFPR modulation (such as FPR2 modulation): including, but not limited tothe treatment of ocular inflammatory diseases: wet and dry age-relatedmacular degeneration (ARMD), dry eye, keratitis, allergic eye diseaseand conditions affecting the posterior part of the eye, such asmaculopathies and retinal degeneration including non-exudative agerelated macular degeneration, exudative age related maculardegeneration, choroidal neovascularization, diabetic retinopathy(proliferative), retinopathy of prematurity (ROP), acute macularneuroretinopathy, central serous chorioretinopathy, cystoid macularedema, and diabetic macular edema; infectious keratitis, herpetickeratitis, corneal angiogenesis, lymphangiogenesis, uveitis, retinitis,and choroiditis such as acute multifocal placoid pigment epitheliopathy,Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis,lyme, tuberculosis, toxoplasmosis), intermediate uveitis (parsplanitis), multifocal choroiditis, multiple evanescent white dotsyndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginouschoroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-and Harada syndrome; vascular diseases/exudative diseases such asretinal arterial occlusive disease, central retinal vein occlusion,cystoids macular edema, disseminated intravascular coagulopathy, branchretinal vein occlusion, hypertensive fundus changes, ocular ischemicsyndrome, retinal arterial microaneurysms, Coat's disease, parafovealtelangiectasis, hemi-retinal vein occlusion, papillophlebitis, centralretinal artery occlusion, branch retinal artery occlusion, carotidartery disease (CAD), frosted branch angiitis, sickle cell retinopathyand other hemoglobinopathies, angioid streaks, familial exudativevitreoretinopathy, and Eales disease; traumatic/surgical conditions suchas sympathetic ophthalmia, uveitic retinal disease, retinal detachment,trauma, conditions caused by laser, conditions caused by photodynamictherapy, photocoagulation, hypoperfusion during surgery, radiationretinopathy, and bone marrow transplant retinopathy; proliferativedisorders such as proliferative vitreal retinopathy and epiretinalmembranes, and proliferative diabetic retinopathy; infectious disorderssuch as ocular histoplasmosis, ocular toxocariasis, presumed ocularhistoplasmosis syndrome (PONS), endophthalmitis, toxoplasmosis, retinaldiseases associated with HIV infection, choroidal disease associate withHIV infection, uveitic disease associate with HIV infection, viralretinitis, acute retinal necrosis, progressive outer retinal necrosis,fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuseunilateral subacute neuroretinitis, and myiasis; genetic disorders suchas retinitis pigmentosa, systemic disorders with associated retinaldystrophies, congenital stationary night blindness, cone dystrophies,Stargardt's disease and fundus flavimaculatus, Best's disease, patterndystrophy of the retinal pigmented epithelium, X-linked retinoschisis,Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti'scrystalline dystrophy, and pseudoxanthoma elasticum; retinal tears/holessuch as retinal detachment, macular hole, and giant retinal tear; tumorssuch as retinal disease associated with tumors, congenital hypertrophyof the retinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigment epitheliitis, systemicinflammatory diseases such as stroke, coronary artery disease,obstructive airway diseases, HIV-mediated retroviral infections,cardiovascular disorders including coronary artery disease,neuroinflammation, neurological disorders, pain and immunologicaldisorders, asthma, allergic disorders, inflammation, systemic lupuserythematosus, psoriasis, CNS disorders such as Alzheimer's disease,arthritis, sepsis, inflammatory bowel disease, cachexia, anginapectoris, post-surgical corneal inflammation, blepharitis, MGD, dermalwound healing, burns, corneal wound healing, rosacea, atopic dermatitis,acne, psoriasis, seborrheic dermatitis, actinic keratoses, viral warts,photoaging rheumatoid arthritis and related inflammatory disorders,alopecia, glaucoma, branch vein occlusion, Best's vitelliform maculardegeneration, retinitis pigmentosa, proliferative vitreoretinopathy(PVR), and any other degenerative disease of either the photoreceptorsor the RPE.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation of the FPR receptor,such as modulation of the FPR2 receptor. Such methods can be performed,for example, by administering to a subject in need thereof atherapeutically effective amount of at least one compound of theinvention, or any combination thereof, or pharmaceutically acceptablesalts, individual enantiomers, and individual diastereomers thereof.

The present invention concerns the use of a compound of Formula I or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of ocular inflammatory diseases including,but not limited to, uveitis, dry eye, keratitis, allergic eye diseaseand conditions affecting the posterior part of the eye, such asmaculopathies and retinal degeneration including non-exudative agerelated macular degeneration, exudative age related maculardegeneration, choroidal neovascularization, diabetic retinopathy, acutemacular neuroretinopathy, central serous chorioretinopathy, cystoidmacular edema, and diabetic macular edema; infectious keratitis,herpetic keratitis, corneal angiogenesis, lymphangiogenesis, retinitis,and choroiditis such as acute multifocal placoid pigment epitheliopathy,Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis,lyme, tuberculosis, toxoplasmosis), intermediate uveitis (parsplanitis), multifocal choroiditis, multiple evanescent white dotsyndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginouschoroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-and Harada syndrome; vascular diseases/exudative diseases such asretinal arterial occlusive disease, central retinal vein occlusion,disseminated intravascular coagulopathy, branch retinal vein occlusion,hypertensive fundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinalvein occlusion, papillophlebitis, central retinal artery occlusion,branch retinal artery occlusion, carotid artery disease (CAD), frostedbranch angiitis, sickle cell retinopathy and other hemoglobinopathies,angioid streaks, familial exudative vitreoretinopathy, and Ealesdisease; traumatic/surgical conditions such as sympathetic ophthalmia,uveitic retinal disease, retinal detachment, trauma, conditions causedby laser, conditions caused by photodynamic therapy, photocoagulation,hypoperfusion during surgery, radiation retinopathy, and bone marrowtransplant retinopathy; proliferative disorders such as proliferativevitreal retinopathy and epiretinal membranes, and proliferative diabeticretinopathy; infectious disorders such as ocular histoplasmosis, oculartoxocariasis, presumed ocular histoplasmosis syndrome (PONS),endophthalmitis, toxoplasmosis, retinal diseases associated with HIVinfection, choroidal disease associate with HIV infection, uveiticdisease associate with HIV infection, viral retinitis, acute retinalnecrosis, progressive outer retinal necrosis, fungal retinal diseases,ocular syphilis, ocular tuberculosis, diffuse unilateral subacuteneuroretinitis, and myiasis; genetic disorders such as retinitispigmentosa, systemic disorders with associated retinal dystrophies,congenital stationary night blindness, cone dystrophies, Stargardt'sdisease and fundus flavimaculatus, Best's disease, pattern dystrophy ofthe retinal pigmented epithelium, X-linked retinoschisis, Sorsby'sfundus dystrophy, benign concentric maculopathy, Bietti's crystallinedystrophy, and pseudoxanthoma elasticum; retinal tears/holes such asretinal detachment, macular hole, and giant retinal tear; tumors such asretinal disease associated with tumors, congenital hypertrophy of theretinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigment epitheliitis, systemicinflammatory diseases such as stroke, coronary artery disease,obstructive airway diseases, HIV-mediated retroviral infections,cardiovascular disorders including coronary artery disease,neuroinflammation, neurological disorders, pain and immunologicaldisorders, asthma, allergic disorders, inflammation, systemic lupuserythematosus, psoriasis, CNS disorders such as Alzheimer's disease,arthritis, sepsis, inflammatory bowel disease, cachexia, anginapectoris, post-surgical corneal inflammation, blepharitis, MGD, dermalwound healing, burns, corneal wound healing, rosacea, atopic dermatitis,acne, psoriasis, seborrheic dermatitis, actinic keratoses, viral warts,photoaging rheumatoid arthritis and related inflammatory disorders,alopecia, glaucoma, branch vein occlusion, Best's vitelliform maculardegeneration, retinitis pigmentosa, proliferative vitreoretinopathy(PVR), and any other degenerative disease of either the photoreceptorsor the RPE.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back of the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may beemployed, including synthetic mono- or diglycerides, fatty acids(including oleic acid), naturally occurring vegetable oils like sesameoil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fattyvehicles like ethyl oleate or the like. Buffers, preservatives,antioxidants, and the like can be incorporated as required.

Pharmaceutical compositions containing invention compounds may be in aform suitable for topical use, for example, as oily suspensions, assolutions or suspensions in aqueous liquids or nonaqueous liquids, or asoil-in-water or water-in-oil liquid emulsions. Pharmaceuticalcompositions may be prepared by combining a therapeutically effectiveamount of at least one compound according to the present invention, or apharmaceutically acceptable salt thereof, as an active ingredient withconventional ophthalmically acceptable pharmaceutical excipients and bypreparation of unit dosage suitable for topical ocular use. Thetherapeutically efficient amount typically is between about 0.001 andabout 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquidformulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 4.5 and 8.0with an appropriate buffer system, a neutral pH being preferred but notessential. The formulations may also contain conventionalpharmaceutically acceptable preservatives, stabilizers and surfactants.Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose cyclodextrin and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar manner an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene. Other excipient componentswhich may be included in the ophthalmic preparations are chelatingagents. The preferred chelating agent is edentate disodium, althoughother chelating agents may also be used in place of or in conjunctionwith it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative  0-0.10 vehicle 0-40 tonicity adjustor 0-10 buffer 0.01-10   pHadjustor q.s. pH 4.5-7.8 antioxidant as needed surfactant as neededpurified water to make 100%

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate application to theeye. Containers suitable for drop wise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution. One package may contain oneor more unit doses. Especially preservative-free solutions are oftenformulated in non-resalable containers containing up to about ten,preferably up to about five units doses, where a typical unit dose isfrom one to about 8 drops, preferably one to about 3 drops. The volumeof one drop usually is about 20-35 μl.

The compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists of the FPR receptor,such as FPR2. Thus, in further embodiments of the invention, there areprovided methods for treating a disorder associated with modulation ofthe FPR receptor, such as modulation of the FPR2 receptor. Such methodscan be performed, for example, by administering to a subject in needthereof a pharmaceutical composition containing a therapeuticallyeffective amount of at least one invention compound. As used herein, theterm “therapeutically effective amount” means the amount of thepharmaceutical composition that will elicit the biological or medicalresponse of a subject in need thereof that is being sought by theresearcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of Formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry. Synthetic Scheme 1, set forth below, illustrates how thecompounds according to the invention can be made.

Compounds within the scope of the invention may be prepared as depictedin Scheme 1. In general, a N-arylhydrazinecarboxamide can be alkylatedwith an aldehyde under reductive amination conditions (e.g., NaCNBH₃) toproduce a N′-substituted N-arylhydrazinecarboxamide. This compound (oran unsubstituted N-arylhydrazinecarboxamide) can be treated with anappropriately substituted acid chloride in the presence of a base or asubstituted carboxylic acid in the presence of a coupling agent like EDCto provide compounds of Formula I.

At this stage, those skilled in the art will appreciate that manyadditional compounds that fall under the scope of the invention coveredby Formula I may be prepared by performing various common chemicalreactions. Details of certain specific chemical transformations areprovided in the Examples that follow. Those skilled in the art will beable to routinely modify and/or adapt the schemes to synthesize anycompounds of the invention covered by Formula I.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand mixtures thereof, including racemic mixtures. Some of the compoundsof the invention may form salts with pharmaceutically acceptable acidsor bases, and such pharmaceutically acceptable salts of the compoundsdescribed herein are also within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of hydrogen ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following Examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following Examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individualdiastereoisomeric forms can be obtained by separation of mixturesthereof in a conventional manner. For example, chromatographicseparation may be employed; chiral chromatography may be performed toseparate individual enantiomers.

Compound names were generated with ACDLab version 12.5; someintermediates' and reagents' names used in the examples were generatedwith softwares such as Chem Bio Draw Ultra version 12.0, ACDLab version12.5 or Auto Nom 2000 from MDL ISIS Draw 2.5 SP1.

In general, characterization of the compounds was performed using NMRspectra, which were recorded on a 300 or 600 MHz Varian NMR spectrometerand acquired at room temperature. Chemical shifts are given in ppmreferenced either to internal TMS or to the solvent signal. All thereagents, solvents, catalysts for which the synthesis is not describedare purchased from chemical vendors such as Sigma Aldrich, Fluka,Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, Trans WorldChemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth,Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex,MIC-scientific, Ltd; however some known intermediates, were preparedaccording to published procedures.

Usually the compounds of the invention were purified by columnchromatography (Auto-column) on Teledyne-ISCO CombiFlash with a silicacolumn, unless noted otherwise.

The following abbreviations are used in the examples:

THF tetrahydrofuranCD₃OD deuterated methanolRT room temperatureCH₂Cl₂ dichloromethaneEtOAc ethyl acetateEtOH ethanolEt₃N triethylamineDMSO-D6 deuterated dimethylsulfonamideK₂CO₃ potassium carbonateHCl hydrochloric acidCD₃CN deuterated acetonitrileNaCNBH₃ sodium borohydrideEtOAc ethyl acetateNaHCO₃ sodium bicarbonateAcOH acetic acidCDCl₃ deuterated chloroformTLC thin layer chromatographyEDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

HOBT 1H-benzotriazol-1-ol

LiOH lithium hydroxideH₂O waterKOH potassium hydroxide

Example 1 Intermediate 1(E)-N-(4-Bromophenyl)-2-(2-methylpropylidene)hydrazinecarboxamide

A mixture of N-(4-bromophenyl)-hydrazinecarboxamide CAS#2646-26-6 (231mg, 1 mmol), isobutyraldehyde CAS#78-84-2 (86 mg, 1.2 mmol), K₂CO₃ (304mg, 1.2 mmol) in THF (5 mL) was stirred for 2 h. The reaction mixturewas diluted with EtOAc (15 mL), washed with dilute aq. HCl (0.5%solution, 5 mL). The EtOAc layer was dried and the solvent was removed.Intermediate 1 was isolated as a white solid.

¹HNMR (CD₃CN) δ: 1.12 (d, J=7.0 Hz, 6H), 2.48-2.59 (m, 1H), 7.18 (d,J=4.98 Hz, 1H), 7.42-7.53 (m, 4H).

Intermediates 3, 5, 7 and 9 were prepared from the correspondinghydrazinecarboxamides and aldehydes, in a similar manner to theprocedure described in Example 1 for Intermediate 1. The results aredescribed below in Table 1.

TABLE 1 Intermediate IUPAC name Hydrazine No. Structure carboxamideAldehyde 3 (E)-N-(4-bromo-2-fluorophenyl)- 2-(2 methylpropylidene)hydrazinecarboxamide  

N-(4-bromo-2- fluorophenyl)- hydrazinecarboxamide CAS 1094561-48-4Isobutyralde- hyde CAS 78-84-2 5 (E)-2-(2-methylpropylidene)-N-(4-(trifluoromethyl)phenyl) hydrazinecarboxamide  

N-[4- (trifluoromethyl) phenyl]- hydrazinecarboxamide CAS 131210-52-1Isobutyralde- hyde CAS 78-84-2 7 (E)-2-propylidene-N-(4-(trifluoromethyl)phenyl) hydrazinecarboxamide  

N-[4- (trifluoromethyl) phenyl]- hydrazinecarboxamide CAS 131210-52-1Propanal CAS 123-38-6 9 (E)-N-(4-bromophenyl)-2-butylidenehydrazinecarboxamide  

N-(4-bromophenyl) hydrazinecarboxamide CAS 2646-26-6 Butanal CAS123-72-8

Example 2 Intermediate 2N-(4-Bromophenyl)-2-isobutylhydrazinecarboxamide

To a mixture of Intermediate 1 (580 mg, 2.05 mmol) and NaCNBH₃ (196 mg,3.1 mmol) in THF (8 mL) was added AcOH (326 mg, 4.1 mmol) and stirred atRT for 6 h. All of the solvent was removed and the crude mixture wasdissolved in EtOAc (50 mL), washed with aq. NaHCO₃ (10% solution, 10mL), brine, dried and the solvent was removed. The crude mixture waspurified by silica gel chromatography, using EtOAc in hexane as eluent.Intermediate 2 was isolated as a white solid.

¹HNMR (CD₃CN) δ: 0.97 (d, J=6.7 Hz, 6H), 1.75-1.87 (m, 1H), 2.61 (d,J=6.7 Hz, 2H), 7.38 (s, 4H).

Intermediates 4, 6, 8 and 10 were prepared from in a similar manner tothe procedure described in Example 2 for Intermediate 2. The results aredescribed below in Table 2.

TABLE 2 From Interm. IUPAC name Interm. No. Structure No. ¹H NMR δ (ppm) 4 N-(4-bromo-2-fluorophenyl)-2- isobutylhydrazinecarboxamide  

3 ¹HNMR (CDCl₃): δ 0.98 (d, J = 6.1 Hz, 6H), 1.70-1.85 (m, 1H), 2.68 (t,J = 6.1 Hz, 2H), 7.13-7.18 (m, 2H), 8.18 (t, J = 8.6 Hz, 1H).  62-isobutyl-N-(4-(trifluoromethyl) phenyl)hydrazinecarboxamide  

5 ¹HNMR (CD₃OD): δ 0.96 (d, J = 6.7 Hz, 6H), 1.70-1.86 (m, 1H), 2.62 (d,J = 7.0 Hz, 2H), 7.50-7.66 (m, 4H).  8 2-propyl-N-(4-(trifluoromethyl)phenyl)hydrazinecarboxamide  

7 ¹HNMR (CD₃OD): δ 1.05 (t, J = 7.0 Hz, 3H), 1.64-1.82 (m, 2H),3.07-3.24 (m, 2H), 7.49-7.64 (m, 2H), 7.64-7.76 (m, 2H). 10N-(4-bromophenyl)-2- butylhydrazinecarboxamide  

9 ¹HNMR (CD₃OD): δ 0.94 (t, J = 7.0 Hz, 3H), 1.30-1.60 (m, 4H), 2.80 (t,J = 7.0 Hz, 2H), 7.38 (s, 4H). 11 N-(4-Bromo-2-fluorophenyl)-2-propylhydrazinecarboxamide  

N-(4- bromo-2- fluorophenyl)- hydrazine carboxamide CAS 1094561- 48-4Propanal CAS 123- 38-6 ¹HNMR (CD₃OD) δ 0.98 (t, J = 7.5 Hz, 3H),1.37-1.71 (m, 2H), 2.78 (t, J = 7.0 Hz, 2H), 7.07-7.46 (m, 2H),7.88-8.17 (m, 1H).

Example 3 Compound 1 Ethyl3-{2[(4-bromophenyl)carbamoyl]hydrazinyl}-3-oxopropanoate

To a solution of N-(4-bromophenyl)hydrazinecarboxamide (CAS#2646-26-6;100 mg, 0.44 mmol), and Et₃N (88 mg, 0.88 mmol) in CH₂Cl₂ (3 mL) and DMF(1 mL) was added 3-chloro-3-oxo-propanoic acid ethyl ester(CAS#36239-09-5; 75 mg, 0.5 mmol). The mixture was stirred at RT for 18h; then the solvent was removed, and the crude mixture was purified bypreparative TLC. Compound 1 was isolated as a white solid.

¹HNMR (CD₃OD) δ: 1.35 (t, J=7.5 Hz, 3H), 3.31 (s, 2H), 4.25 (q, J=7.5Hz, 2H), 7.40 (s, 4H).

Example 4 Compound 23-{2-[(4-Bromophenyl)carbamoyl]hydrazinyl}-2,2-dimethyl-3-oxopropanoicAcid

A mixture of N-(4-bromophenyl)hydrazinecarboxamide (CAS#2646-26-6; 100mg, 0.44 mmol), EDC (130 mg, 0.66 mmol), HOBT (90 mg, 0.66 mmol),4-methyl morpholine (131 mg, 1.32 mmol) and dimethylmalonic acid (58 mg,0.44 mmol) in CH₂Cl₂ (5 mL) was stirred at RT for 18 h. The solvent wasremoved and the crude mixture was purified by preparative TLC. Compound2 was isolated as a white solid.

¹HNMR (CD₃OD) δ: 1.31 (s, 6H), 7.42 (br s, 4H).

Compounds 3, 4 and 6 were prepared in a similar manner to the proceduredescribed in Example 4 for Compound 2. The results are shown below inTable 3.

TABLE 3 Cmpd. IUPAC name Starting ¹H NMR δ No. Structure materials (ppm)3 4-{2-[(4- bromophenyl)carbamoyl] hydrazinyl}-2,2-dimethyl-4-oxobutanoic acid  

N-(4- bromophenyl) hydrazinecarbox amide CAS 2646-26-6 2,2-dimethylButanedioic acid CAS 597-43-3 ¹HNMR (CD₃OD) δ: 1.38 (s, 6H), 2.68 (s,2H), 7.35 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H). white solid 4methyl 2-(2-{2-[(4-bromophenyl) carbamoyl]hydrazinyl}-2-oxoethyl)-2-propylpentanoate  

N-(4- bromophenyl) hydrazinecarbox amide CAS 2646-26-6 butanedioic acid,2,2- dipropyl-,1- methyl ester CAS 664304-90-9 ¹HNMR (CD₃OD) δ: 0.91 (brs, 6H), 1.16-1.36 (m, 4H), 1.59- 1.75 (m, 4H), 2.57 (s, 2H), 3.67 (s,3H), 7.38 (s, 4H). 6 4-{2-[(4-bromophenyl) carbamoyl]hydrazinyl}-2,2-diethyl-4-oxobutanoic acid  

N-(4- bromophenyl) hydrazinecarbox amide CAS 2646-26-6 3,3-diethyldihydro-2, 5-Furandione CAS 2840-69-9 ¹HNMR (CD₃OD) δ: 0.91 (t, J= 7.5 Hz, 6H), 1.76 (q, J = 7.5 Hz, 2H), 2.53 (s, 2H), 7.37 (m, 4H).

Example 5 Compound 52-[2-(2-{[(4-Bromophenyl)amino]carbonyl}hydrazino)-2-oxoethyl]-2-propylpentanoicAcid

A mixture of Compound 4 (280 mg, 0.65 mmol) LiOH—H₂O (1 M solution, 2,mL) and methanol (5 mL) was stirred for 5 h at RT. The reaction wasquenched with 10% HCl solution (2 mL), extracted with EtOAC, the organiclayer was washed with brine, dried and solvent removed. The crudeproduct was purified by preparative TLC. Compound 5 was isolated as alight yellow solid.

¹HNMR (CD₃OD) δ: 0.93 (br s, 6H), 1.29 (br s, 4H), 1.65 (br s, 4H), 2.70(br s, 2H), 7.23-7.51 (m, 4H).

Example 6 Compound 7 Ethyl4-{2-[(4-Bromophenyl)carbamoyl]-1-(2-methylpropyl)hydrazinyl}-4-oxobutanoate

To a cold (0° C.) mixture of Intermediate 2 (183 mg, 0.63 mmol), Et₃N(77 mg, 0.77 mmol) in dioxane (4 mL) was added 4-chloro-4-oxo-butanoicacid ethyl ester (CAS#14794-31-1; 115 mg, 0.69 mmol). The mixture wasstirred at RT for 2 h. The reaction was diluted with EtOAc (50 mL),washed with aq. NaHCO₃ (10 mL), dried and solvent removed. The crudeproduct was recrystallized from hot methanol. Compound 7 was isolated asa white solid.

¹HNMR (CD₃CN): δ 0.93 (br d, 6H), 1.23 (t, J=7.3 Hz, 3H), 1.82-1.95 (m,1H), 2.54 (t, J=6.1 Hz, 2H), 2.62 (br. d, 2H), 2.78 (t, J=6.1 Hz, 2H),4.12 (q, J=7.3 Hz, 2H), 7.37-7.49 (m, 4H).

Compounds 9, 11, 13, 15 and 16 were prepared in a similar manner to theprocedure described in Example 6 for Compound 7. The results aredescribed below in Table 4.

TABLE 4 Compound IUPAC name Interm. ¹H NMR δ No. Structure No (ppm)  9ethyl 4-{2-[(4-bromo-2- fluorophenyl)carbamoyl]-1-(2-methylpropyl)hydrazinyl}-4- oxobutanoate  

 4 ¹HNMR (CD3OD): δ 0.91 (br. S, 6H), 1.21 (t, J = 7.2 Hz, 3H),1.82-2.05 (m, 1H), 2.50- 2.70 (br. S, 4H), 2.75-3.00 (br. s, 2H), 4.09(q, J = 7.2 Hz, 2H), 7.20-7.35 (m, 2H), 7.90 (br. t, 1H). 11 ethyl4-[1-(2-methylpropyl) 2{[4- (trifluoromethyl)phenyl]carbamoyl}hydrazinyl]-4- oxobutanoate  

 6 ¹HNMR (CD₃OD): δ 0.93 (br. S, 6H), 1.23 (t, J = 7.2 Hz, 3H),1.90-2.05 (m, 1H), 2.50- 2.70 (br. S, 4H), 2.75-3.00 (br. s, 2H), 4.12(q, J = 7.2 Hz, 2H), 7.47-7.75 (m, 4H). 13 ethyl4-oxo-4-(1-propyl-2-{[4- (trifluoromethyl)phenyl]carbamoyl}hydrazinyl)butanoate  

8 ¹HNMR (CD₃OD): δ 0.92 (t, J = 7.3 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H),1.45-1.71 (m, 2H), 2.50-2.82 (br. s, 4H), 3.30- 3.40 (br. s, 2H), 4.12(q, J = 7.0 Hz, 2H), 7.46-7.74 (m, 4H). 15 ethyl 4-{2-[(4-bromophenyl)carbamoyl]-1- butylhydrazinyl}-4-oxobutanoate  

10 ¹HNIMR (CD₃OD): δ 0.93 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H),1.30-1.40 (m, 2H), 1.50-1.62 (m, 2H), 2.50- 2.70 (br. s, 4H), 2.70-2.90(br. s, 2H), 4.12 (q, J = 7.2 Hz, 2H), 7.40 (s, 4H). 16 ethyl4-{2-[(4-bromo-2- fluorophenyl)carbamoyl]-1-propylhydrazinyl}-4-oxobutanoate  

Intermediate 11 ¹HNMR (CD₃OD): δ 0.91 (t, J = 7.3 Hz, 3H), 1.22 (t, J =7.2 Hz, 3H), 1.55-1.70 (m, 2H), 2.50-2.80 (br s, 4H), 3.20- 3.40 (br s,2H), 4.10 (q, J = 7.2 Hz, 2H), 7.26 (dd, J = 1.2, 8.8 Hz, 1H), 7.33 (dd,J = 2.1, 10.6 Hz, 1H), 7.87 (br s, 1H).

Example 7 Compound 84-{2-[(4-Bromophenyl)carbamoyl]-1-(2-methylpropyl)hydrazinyl}-4-oxobutanoicAcid

A mixture of Compound 7 (90 mg, 0.22 mmol), KOH—H₂O (1 M solution, 1mL), EtOH (1 mL) and dioxane (1 mL) was stirred at RT for 3 h. About 80%of the solvent was removed, the crude mixture cooled to −78° C. andacidified with aq. HCl. Compound 8 was collected as a white solid.

¹HNMR (DMSO-D₆): δ 0.93 (br s, 6H), 1.82-1.99 (m, 1H), 2.53 (br. s, 2H),2.85 (br. s, 2H), 2.30 (br. s, 2H), 7.55 (s, 4H).

Compounds 10, 12, 14 and 17 were prepared in a similar manner to theprocedure described in Example 7 for Compound 8. The results aredescribed below in Table 5.

TABLE 5 Compound IUPAC name Starting ¹H NMR δ No. Structure Compound(ppm) 10 4-{2-[(4-bromo-2- fluorophenyl)carbamoyl]-1-(2-methylpropyl)hydrazinyl}-4- oxobutanoic acid  

9 ¹HNMR (CD₃OD): δ 0.91 (br. S, 6H), 1.94 (br. s, 1H), 2.57 (br. S, 4H),2.98 (br. s, 2H), 7.20- 7.35 (m, 2H), 7.87 (br. t, 1 H). 124-[1-(2-methylpropyl)-2-{[4- (trifluoromethyl)phenyl]carbamoyl}hydrazinyl]-4-oxobutanoic acid  

11 ¹HNMR (CD₃OD): δ 0.92 (br. s, 6H), 1.92-2.02 (m, 1H), 2.45-2.65 (br.s, 4H), 2.70- 2.80 (br., s, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H). 14 4-oxo-4-(1-propyl-2-{[4-(trifluoromethyl)phenyl]carbamoyl} hydrazinyl)butanoic acid  

13 ¹HNMR (CD₃OD): δ 0.92 (t, J = 7.3 Hz, 3H), 1.49- 1.74 (m, 2H),2.43-2.80 (br. s, 4H), 3.30- 3.40 (br. s, 2H), 7.47-7.60 (m, 2H),7.60-7.73 (m, 2H). 17 4-{2-[(4-bromo-2- fluorophenyl)carbamoyl]-1-propylhydrazinyl}-4- oxobutanoic acid  

16 ¹HNIMR (CD₃OD): δ 0.91 (t, J = 7.2 Hz, 3H), 1.55-1.70 (m, 2H), 2.50-2.80 (br s, 4H), 3.20-3.40 (br s, 2H), 7.28 (d, J = 8.8 Hz, 1H), 7.35(dd, J = 1.9, 10.4 Hz, 1H), 7.85 (br s, 1H).

Biological Data

Compounds of Formula I modulate FPR activity. For example, the data setforth in Table 6 below show that compounds of Formula I modulate FPR2activity. HEK-Gα16 and CHO-Gα16 cells stably expressing FPR2 werecultured in (F12, 10% FBS, 1% PSA, 400 μg/ml geneticin and 50 μg/mlhygromycin) and HEK-Gqi5 cells stable expressing FPR2 were cultured in(DMEM high glucose, 10% FBS, 1% PSA, 400 μg/ml geneticin and 50 μg/mlhygromycin). In general, the day before the experiment, 18,000cells/well were plated in a 384-well clear bottom poly-D-lysine coatedplate. The following day, the screening compound-induced calciumactivity was assayed on the FLIPR^(Tetra). The drug plates were preparedin 384-well microplates using the EP3 and the MuItiPROBE robotic liquidhandling systems. Compounds were tested at concentrations ranging from0.61 to 10,000 nM. Results are expressed as EC₅₀ (nM) and efficacyvalues.

TABLE 6 EC₅₀ nM Compound IUPAC name (% Efficacy) ethyl3-{2-[(4-bromophenyl)carbamoyl]hydrazinyl}-3- 750  oxopropanoate (100) 3-{2-[(4-bromophenyl)carbamoyl]hydrazinyl}-2,2- 5212 dimethyl-3-oxopropanoic acid (73)4-{2-[(4-bromophenyl)carbamoyl]hydrazinyl}-2,2- 602 dimethyl-4-oxobutanoic acid (86) methyl2-(2-{2-[(4-bromophenyl)carbamoyl]hydrazinyl}- 462-oxoethyl)-2-propylpentanoate (89)2-(2-{2-[(4-bromophenyl)carbamoyl]hydrazinyl}-2- 215 oxoethyl)-2-propylpentanoic acid (87)4-{2-[(4-bromophenyl)carbamoyl]hydrazinyl}-2,2- 421 diethyl-4-oxobutanoic acid (73) ethyl4-{2-[(4-bromophenyl)carbamoyl]-1-(2- 31methylpropyl)hydrazinyl}-4-oxobutanoate (100) 4-{2-[(4-bromophenyl)carbamoyl]-1-(2- 12methylpropyl)hydrazinyl}-4-oxobutanoic acid (100)  ethyl4-{2-[(4-bromo-2-fluorophenyl)carbamoyl]-1-(2- 3659 methylpropyl)hydrazinyl}-4-oxobutanoate (76)4-{2-[(4-bromo-2-fluorophenyl)carbamoyl]-1-(2- 339 methylpropyl)hydrazinyl}-4-oxobutanoic acid (99) ethyl4-[1-(2-methylpropyl)-2-{[4- 57(trifluoromethyl)phenyl]carbamoyl}hydrazinyl]-4- (94) oxobutanoate4-[1-(2-methylpropyl)-2-{[4- 21(trifluoromethyl)phenyl]carbamoyl}hydrazinyl]-4- (98) oxobutanoic acidethyl 4-oxo-4-(1-propyl-2-{[4- 35(trifluoromethyl)phenyl]carbamoyl}hydrazinyl)butanoate (98)4-oxo-4-(1-propyl-2-{[4- 28(trifluoromethyl)phenyl]carbamoyl}hydrazinyl)butanoic (97) acid ethyl4-{2-[(4-bromophenyl)carbamoyl]-1- 34 butylhydrazinyl}-4-oxobutanoate(100)  ethyl 4-{2-[(4-bromo-2-fluorophenyl)carbamoyl]-1 - 34propylhydrazinyl}-4-oxobutanoate (100) 4-{2-[(4-bromo-2-fluorophenyl)carbamoyl]-1- 29propylhydrazinyl}-4-oxobutanoic acid (100) 

What we claim is:
 1. A compound represented by Formula I:

R¹ is H, optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl, optionallysubstituted C₃₋₈cycloalkyl, optionally substituted C₆₋₁₀aryl, optionallysubstituted heterocycle, halogen, —OR¹⁰, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—CN, —C(O)R¹¹, amine, amide, urea, sulfonamide, sulfone, sulfoxide,sulfide, sulfonic acid, nitro, phosphate or phosphonic acid; R² is H,optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀aryl, optionallysubstituted heterocycle, halogen, —OR¹⁰, —C₂₋₆alkenyl, —C₂₋₆ alkynyl,—CN, —C(O)R¹¹, amine, amide, urea, sulfonamide, sulfone, sulfoxide,sulfide, sulfonic acid, nitro, phosphate or phosphonic acid; R³ is H,optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl, optionally substitutedC₃₋₈cycloalkyl, optionally substituted C₆₋₁₀aryl, optionally substitutedheterocycle, halogen, —OR¹⁰, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —CN, —C(O)R¹¹,amine, amide, urea, sulfonamide, sulfone, sulfoxide, sulfide, sulfonicacid, nitro, phosphate or phosphonic acid; R⁴ is H, optionallysubstituted C₁₋₆alkyl, C₁₋₆haloalkyl, optionally substitutedC₃₋₈cycloalkyl, optionally substituted C₆₋₁₀aryl, optionally substitutedheterocycle, halogen, —OR¹⁰, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, —CN,—C(O)R¹¹, amine, amide, urea, sulfonamide, sulfone, sulfoxide, sulfide,sulfonic acid, nitro, phosphate or phosphonic acid; R⁵ is H, optionallysubstituted C₁₋₆alkyl, C₁₋₆haloalkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted C₆₋₁₀aryl, optionally substitutedheterocycle, halogen, —OR¹⁰, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —CN, —C(O)R¹¹,amine, amide, urea, sulfonamide, sulfone, sulfoxide, sulfide, sulfonicacid, nitro, phosphate or phosphonic acid; R⁶ is H or optionallysubstituted C₁₋₆alkyl; R⁷ is H or optionally substituted C₁₋₆alkyl; R⁸is H or optionally substituted C₁₋₆alkyl; R⁹ is H or optionallysubstituted C₁₋₆alkyl; a is 0, 1, 2 or 3; R¹⁰ is —OH or optionallysubstituted C₁₋₆alkyl; R¹¹ is —OH, —OC₁₋₆alkyl or optionally substitutedC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof; provided thatthe compound is not of structure:


2. The compound according to claim 1, wherein: R¹ is H or halogen; R² isH or halogen; R³ is C₁₋₆haloalkyl or halogen; R⁴ is H or halogen; R⁵ isH or halogen; and R⁹ is H or optionally substituted C₁₋₆alkyl.
 3. Thecompound according to claim 1, wherein: R¹ is H or halogen; R² is H orhalogen; R³ is C₁₋₆haloalkyl; R⁴ is H or halogen; R⁵ is H or halogen;and R⁹ is H or optionally substituted C₁₋₆alkyl.
 4. The compoundaccording to claim 1, wherein: R¹ is H or halogen; R² is H or halogen;R³ is halogen; R⁴ is H or halogen; R⁵ is H or halogen; and R⁹ is H oroptionally substituted C₁₋₆alkyl.
 5. The compound according to claim 1,wherein: R¹ is H or halogen; R² is H or halogen; R³ is C₁₋₆haloalkyl orhalogen; R⁴ is H or halogen; R⁵ is H or halogen; and R⁹ is H.
 6. Thecompound according to claim 1, wherein: R¹ is H or halogen; R² is H orhalogen; R³ is C₁₋₆haloalkyl or halogen; R⁴ is H or halogen; R⁵ is H orhalogen; R⁹ is H; and a is 0 or
 1. 7. The compound according to claim 1,wherein: R¹ is H or halogen; R² is H or halogen; R³ is C₁₋₆haloalkyl; R⁴is H or halogen; R⁵ is H or halogen; and R⁹ is H.
 8. The compoundaccording to claim 1, wherein: R¹ is H or halogen; R² is H or halogen;R³ is C₁₋₆haloalkyl; R⁴ is H or halogen; R⁵ is H or halogen; and R⁹ isoptionally substituted C₁₋₆alkyl.
 9. The compound according to claim 1,wherein: R¹ is H or halogen; R² is H or halogen; R³ is halogen; R⁴ is Hor halogen; R⁵ is H or halogen; and R⁹ is H.
 10. The compound accordingto claim 1, wherein: R¹ is H or halogen; R² is H or halogen; R³ ishalogen; R⁴ is H or halogen; R⁵ is H or halogen; and R⁹ is optionallysubstituted C₁₋₆ alkyl.
 11. The compound according to claim 1, wherein:R¹ is H or halogen; R² is H; R³ is C₁₋₆haloalkyl or halogen; R⁴ is H; R⁵is H or halogen; R⁶ is optionally substituted C₁₋₆alkyl; R⁷ is H; R⁸ isH; R⁹ is H or optionally substituted C₁₋₆ alkyl; and a is 0 or
 1. 12.The compound according to claim 1, selected from:

and pharmaceutically acceptable salts thereof.
 13. A pharmaceuticalcomposition comprising as active ingredient a therapeutically effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable diluent or carrier.
 14. The pharmaceutical compositionaccording to claim 13 comprising as active ingredient a therapeuticallyeffective amount of a compound of claim 12.